This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastric cancer, a major cause of mortality worldwide, is usually preceded by pylori infection. Recognition of H. pylori's role in gastric cancer development affords novel opportunities to study the molecular and cellular events of gastric carcinogenesis and discover novel gastric cancer biomarkers. These insights may lead to the identification of patients at highest gastric cancer risk, and have prognostic and therapeutic applications. In the first COBRE funding cycle, we evaluated the mechanisms and consequences of p27 down-regulation by H. pylori, garnering R01 funding to continue. This new pilot proposal builds upon our recent analysis of the gastric epithelial cell transcriptome of H. pylori infection in vivo. We used laster capture microdissection and gene chips identified, 2 novel related genes (gastrokine [GKN] 1 and 2) that were highly significantly decreased in expression in H. pylori infected tissues were selected for further study. Our focus on GKN1 and 2 is because (i) Gastrokine 2 (GKN2) was the gene whose expression was the most down-regulated by H. pylori, (ii) decreased expression of gastrokines 1 &2 were recently reported in small gastric cancer series by others, and confirmed by us to be lost in a large proportion of cases in gastric cancer, and (iii) biological plausibility-GKN2 interacts with trefoil factor family proteins involved in gastric mucosal repair, H. pylori adherence and carcinogenesis. We hypothesize that (1) GKN1 and GKN2 are regulated by H. pylori and act as gastric cancer tumor suppressors: and (2) expression of GKN1 and GKN2 may serve as gastric cancer biomarkers. These hypotheses will be tested over 2 years by (1) examining the cellular effects of alterations in GKN1 and GKN2 in gastric cells in vitro and in vivo and (2) by evaluating the utility of GKN1 and GKN2 as biomarkers of gastric cancer susceptibility in a prospectively clinical study of H. pylori-infected patients and in a mouse model of H. pylori-induced gastric cancer.